When administering a drug buccally (i.e., by absorption of the drug through the buccal tissues of the mouth) a number of conditions are present which makes it difficult to effectively deliver drug in a therapeutically effective amount for a prolonged period of time (e.g., for periods greater than several minutes). For example, when a patient is given a drug-containing lozenge, there is a natural tendency to suck and chew on the lozenge thereby effectively reducing the time period during which the drug can be buccally administered by the lozenge. This has been a particular problem in treating diseases of the mouth which require constant local administration of the drug. In addition, the action of saliva and swallowing by the patient effectively reduces the concentration of drug along the buccal membranes of the oral cavity and further causes much of the drug to be swallowed, in many cases rendering it inactive upon encountering the low pH environment of the stomach. One such disease that requires constant administration of drug is xerostomia.
Xerostomia is a condition in which salivary glands do not produce sufficient quantities of saliva. Cases of xerostomia may vary from the mild, in which only slight dryness is experienced, to severe cases in which the patient will have serious problems with swallowing, speech, digestion, and the like. There are a number of causes of xerostomia, including physiological, psychological, pharmacological (e.g., as a common side effect of many medications), or as a result of radiotherapy.
Until recently, the treatments for xerostomia have had significant drawbacks. For example, symptoms of mild xerostomia can be somewhat alleviated by consumption of fluids, hard candy, and throat lozenges. However, fluids or candy are typically not effective with more severe cases of xerostomia, and more importantly, they do not provide long lasting relief.
Another recommended method of treating xerostomia buccally is by placing 2-4 drops of pilocarpine ophthalmic drops on the tongue four times daily, Epstein et al., "Management of Xerostomia," Scientific Journal, Vol. 58, No. 2, February 1992. Unfortunately, when pilocarpine is administered, either by drops or by a mouthrinse, the drug is cleared from the mouth in a matter of minutes, U.S. Pat. No. 4,209,505.
U.S. Pat. No. 4,983,378 describes the delivery of Yerba Santa extract by gum or lozenge form. While the duration of drug delivery is increased somewhat using slowly dissolving lozenges, typically these release drug for no more than about 15 to 20 minutes. Accordingly, these dosage forms require frequent repetitive dosing in order to effectively treat the condition.
In response to the problem of short duration of drug delivery from rinses and lozenges, it is necessary to extend delivery over a long period of time in a predictable fashion. Previous devices utilize, in one form or another, release rate controlling barriers or membranes interposed between the source of the drug and the environment of use to control release rates. While such devices can be designed to produce extremely precise release rates, their structure is relatively complex, which complexity adds to the cost of the device.
In particular, the use of an osmotic pump to deliver mediation to the buccal tissues has been taught. See U.S. Pat. Nos. 5,053,032 and 5,021,053. Unfortunately, the membrane surrounding the osmotic pump can burst when aggressively chewed, thus releasing the entire dose present in the device. This presents a safety problem, when the release of the entire dose of a drug can cause severe adverse side effects. Additionally, an osmotic pump device requires a sufficient amount of water to operate and drive the pump. In patients, who do not produce sufficient quantities of saliva, the osmotic pump device will not operate.
Other devices have been taught where precise control is not required. It has been known to disperse the biologically active agent in a polymeric matrix which is then placed in the environment of use and the active agent released therefrom by diffusion. The rate of release of a dispersed active agent at a concentration equal to or less than saturation from such systems normally will vary inversely with the square root of time (t.sup.-1/2) that the system is in operation. U.S. Pat. No. 4,069,307. Such systems, accordingly, are characterized by an initial high release rate which then decreases relatively rapidly and continuously over the lifetime of the device. This is due to the depletion of the drug from the matrix which reduces the concentration gradient between the matrix and the surrounding environment. Such devices do not provide a sustained controlled rate of delivery for a prolonged period of time.
Since simply dispersing an active agent through a matrix has significant safety and cost advantages, various approaches have been proposed to improve the release characteristics without resorting to the use of rate controlling membranes. Geometrical approaches have been suggested, Controlled Release of Bioactive Materials, Edited by Richard Baker, p. 177-187, Academic Press, New York (1980), as have systems based on the relationship between solubility and diffusion coefficient, Chien et al., Controlled Drug Release From Polymeric Delivery Devices II: Differentiation Between Partition Controlled and Matrix Controlled Drug Release Mechanisms, J. Pharm. Sci., Vol. 63, No. 4, p. 515-519 (April 1974). It has also been proposed to vary the concentration between the core and the outer layer or to have a depleted zone containing the agent at a concentration no greater than saturation and a non-depleted zone containing the agent dispersed in the matrix at a uniform concentration greater than saturation, U.S. Pat. No. 4,564,364. Other proposed devices have a plurality of reservoirs containing drug distributed through a matrix, U.S. Pat. No. 3,921,636.
While these approaches can improve the release characteristics of the device, the manufacturing techniques required to obtain the desired concentration gradient, either by forming separate compositions having different concentrations of solute dispersed in the matrix and thereafter sequentially forming the end item, by sequentially depositing additional amounts of the active agent onto a substrate, by extracting the surface of the finished device, or by forming microcapsules around the drug reservoir; may closely approach the cost associated with manufacturing a rate controlling membrane system having superior properties.
Thus, there has been a clear need in the art of treating oral disease, such as xerostomia, for a dosage form which is able to continuously deliver therapeutically effective amounts of drug or other beneficial agent into the oral cavity for extended periods of time, i.e. periods greater than about 15 to 20 minutes, with a minimal amount of water and low cost of manufacturing.